Endocrine Abstracts (2011) 26 S26.2

The role of IGFBPs in the tissue-specific actions of IGFs

J M P Holly & C M Perks

University of Bristol, Bristol, UK.

The IGFs are present ubiquitously at very high levels throughout the body and affect virtually every aspect of cell function. These high levels are maintained due to their association with 6 distinct binding proteins (IGFBP-1 to -6) which specifically bind IGFs (but not insulin). The IGFs are not stored within any cells but are stored in the circulation due to their binding to IGFBP-3 which then results in its association with a large glycoprotein, the acid labile subunit (ALS). This large ternary complex has limited ability to cross the capillary endothelium dramatically slowing clearance and maintaining a large circulating reservoir of IGFs which can then be made available to tissues when required by the action of specific proteases. In the tissues the 6 IGFBPs bind the IGFs with affinity greater than that of their cell surface receptors enabling them to tightly control tissue activity. Each IGFBP then has specific proteases which cleaves the IGFBP lowering the affinity with which IGFs are bound and increasing their availability to receptors. The IGFBPs can also associate with other specific proteins and proteoglycans in the matrix and on cell surfaces enabling them to concentrate IGFs in the pericellular environment and enhance IGF actions or reduce down-regulation of cell IGF receptors. Each IGFBP can also affect cell functions independently of the IGF-receptors by interacting with specific cellular proteins and modulating other signalling pathways, such as that of TGF-β and EGF. The IGFBPs, their proteases and their other interacting proteins are present in different tissues in various combinations and are all differentially regulated. The IGFBPs can therefore confer considerable specificity on the ubiquitously present IGFs: enabling tissue-specific actions according to the local context.

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